Typically, prenatal diagnostic tests include fetal karyotype analysis. Traditional methods rely on invasive techniques, such as amniocentesis and chorionic villus sampling, both of which incur some risk of fetal injury or loss. See, e.g., Sundberg, et. al., Lancet, 350: 697-703 (1997). As an alternative to sampling the fetal environment, current techniques often involve isolating fetal cells from maternal blood. See, e.g., Liou, et al, Ann. N.Y. Acad. Sci., 7: 237-241 (1994). Nucleated red blood cells are reported to be a good cell type for analysis because those cells have sufficient DNA for analysis, they are present in maternal blood, they are easily identified based on their morphology, and they have a known gestational life span. Lamvu, et al., Obstet. Gynecol. Surv., 52: 433-437 (1997).
Whether taken from chorionic villi, amniotic fluid, or maternal blood, samples commonly are karyotyped to determine chromosomal abnormalities, such as aneuploidies. Cytogenic techniques with high-resolution banding frequently have been used for diagnosis of gross fetal chromosomal abnormalities. However, small chromosomal abnormalities (i.e., those involving changes of less than about 5 million base pairs) are difficult, if not impossible, to detect using gross cytogenetic tests. Accordingly, preferred techniques for diagnosis of both gross abnormalities and smaller nucleic acid mutations include molecular cytogenetic techniques, such as fluorescence in situ hybridization (FISH). For example, fetal cells from maternal blood have been isolated using density gradient centrifugation, and magnetic cell sorting, and counted using FISH. Jansen, et al., Prenat. Diagn., 17(10): 953-959 (1997). The FISH technique, either alone, or in conjunction with fluorescent polymerase chain reaction, has become a primary technique for diagnosis of prenatal genetic abnormalities in samples from chorionic villi, amniotic fluid, blood, and whole cells, obtained, for example, from transcervical sampling. While FISH is adequate for screening for common chromosomal aneuploidies, such as trisomy 21, trisomy 13, XXY, and monosomy X, it is not useful for detecting chromosome deletions or rearrangements, which are common in, for example, chromosomes 12, 14, and 17. Lamvu, supra.
Accordingly, further techniques are necessary and desirable for detecting fetal chromosomal abnormalities. Such techniques are presented herein.